Simvastatin boosts neutrophil apoptosis and ameliorates secondary brain injury following intracerebral hemorrhage via LXA4/FPR2/p38 MAPK pathway

Statins, in addition to their well-known lipid-lowering effects, have also shown a wide range of neuroprotective effects in recent years. We previously found that simvastatin effectively attenuated intracerebral hemorrhage (ICH)-induced secondary brain injury in rats. This study aims to elucidate the underlying mechanism. The animal model was established in adult male Sprague–Dawley rats by an injection of autologous blood, then randomly treated with simvastatin or vehicle. Then, a series of experiments were conducted to investigate the involvement of lipoxin A4 (LXA4) / formyl-peptide receptor 2 (FPR2) / p38 MAPK signaling pathway in simvastatin-triggered neutrophil apoptosis. Results show that simvastatin significantly elevated the level of LXA4 (an endogenous FPR2 agonist) in plasm in early stage of ICH. Exogenous LXA4 administration effectively promoted circulating neutrophil apoptosis, reduced the neutrophil count in both peripheral blood and perihematomal area, as well as ameliorated neuroinflammation and brain injury after ICH, which in line with the effect of simvastatin. Moreover, similar to simvastatin, the exogenous LXA4 markedly down-regulated the phosphorylation level of p38 and the Mcl-1/Bax ratio (the decreased ratio represents pro-apoptosis) in circulating neutrophils of ICH rat. Notably, all above effects of simvastatin on ICH were significantly abolished by Boc-2, a selective antagonist for FPR2. Moreover, simvastatin led to a similar reduction of Mcl-1/Bax ratio as SB203580 (p38 MAPK inhibitor), but it was abolished by P79350 (p38 MAPK agonist). Collectively, these results suggest that simvastatin boosts neutrophils apoptosis and alleviates subsequent neuroinflammation following ICH may via upregulating LXA4 in plasma through the FPR2/p38 MAPK signaling pathway.